Submissions for variant NM_002834.5(PTPN11):c.855T>G (p.Phe285Leu)

dbSNP: rs397516810

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037665	SCV000061327	pathogenic	Noonan syndrome	2012-02-27	criteria provided, single submitter	clinical testing	The Phe285Leu variant has been reported in the literature in one sporadic incide nce of Noonan syndrome (Hung 2007). This variant has also been identified in on e individual with clinical features of Noonan syndrome by our laboratory. Addit ionally, a different nucleotide substitution (c.853T>C) resulting in the same am ino acid change has also been identified in several individuals with the clinica l features of Noonan syndrome as well as Noonan-like/multiple giant-cell lesion syndrome both in the literature and by our laboratory (Tartaglia 2002, Nystrom 2 008, Jafarov 2005, Lee 2005, LMM unpublished data). The c.853T>C variant has als o been observed to have occurred de novo in sporadic cases of Noonan syndrome. In summary, the Phe285Leu variant meets our criteria to be classified as pathoge nic. The presence of a heterozygous pathogenic variant in PTPN11 is consistent w ith a diagnosis of Noonan syndrome but this information should be reconciled wit h the complete clinical history of this individual.
GeneDx	RCV000159052	SCV000208994	pathogenic	not provided	2023-05-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 17339163, 19120036, 11992261, 28870985, 29907801, 29493581, 30050098, 32164556)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587757	SCV000698083	pathogenic	Noonan syndrome 3	2016-02-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687570	SCV000815146	pathogenic	RASopathy	2024-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 285 of the PTPN11 protein (p.Phe285Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 11992261, 15996221, 16358218, 17339163, 18470943, 21106241, 23321623, 23771920). ClinVar contains an entry for this variant (Variation ID: 44615). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PTPN11 protein function. This variant disrupts the p.Phe285 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11992261, 15996221, 16358218, 18470943, 21106241, 23321623, 23771920). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
MGZ Medical Genetics Center	RCV002288537	SCV002579183	pathogenic	Noonan syndrome 1	2022-05-18	criteria provided, single submitter	clinical testing